The present invention relates to novel benzimidazoles, their preparation and their use as inhibitors of the enzyme poly-(ADP-ribose) polymerase or PARP (EC 2.4.2.30) for producing drugs.
Poly(ADP-ribose) polymerase (PARP) or, as it is also known, poly(ADP-ribose) synthase (PARS), is a regulatory enzyme found in cell nuclei (K. Ikai et al., J. Histochem. Cytochem. 1983, 31, 1261-1264). It is assumed that PARP is involved in the repair of DNA breaks (M. S. Satoh et al., Nature 1992, 356, 356-358). Damage or breaks in DNA strands activate the enzyme PARP which, when it is activated, catalyzes the transfer of ADP-ribose from NAD (S. Shaw, Adv. Radiat. Biol., 1984, 11, 1-69). During this, nicotinamide is released from NAD. Nicotinamide is converted back into NAD by other enzymes with consumption of the energy carrier ATP. Overactivation of PARP would accordingly result in a nonphysiologically large consumption of ATP, and this leads in the extreme case to cell damage and cell death.
It is known that free radicals such as superoxide anion, NO and hydrogen peroxide may lead to DNA damage in cells and thus activate PARP. The formation of large amounts of free radicals is observed in a number of pathophysiological states, and it is assumed that this accumulation of free radicals leads or contributes to observed cell or organ damage. This includes, for example, ischemic states of organs as in stroke, myocardial infarct (C. Thiemermann et al., Proc. Natl. Acad. Sci. USA, 1997, 94, 679-683) or ischemia of the kidneys, but also reperfusion damage has occurred, for example, after lysis of myocardial infarct (see above: C. Thiemermann et al.). Inhibition of the enzyme PARP might accordingly be a means of at least partly preventing or moderating this damage. PARP inhibitors might thus represent a novel therapeutic principle for treating a number of diseases.
The enzyme PARP influences the repair of DNA damage and might thus also play a part in the therapy of cancers since a greater action potential on tumor tissue was observed (G. Chen et al. Cancer Chemo. Pharmacol. 1988, 22, 303) in combination with substances with cytostatic activity. Nonlimiting examples of tumors are leukemia, glioblastomas, lymphomas, melanomas and carcinomas of the breast and cervix.
In addition, it has been found that PARP inhibitors may show an immunosuppressant effect (D. Weltin et al. Int.J.Immunopharmacol. 1995, 17, 265-271).
It has likewise been discovered that PARP is involved in immunological disorders or diseases in which the immune system plays an important part, such as, for example, rheumatoid arthritis and septic shock, and that PARP inhibitors may show a beneficial effect on the course of the disease (H. Krxc3x6ger et al. Inflammation 1996, 20, 203-215; W. Ehrlich et al. Rheumatol. Int. 1995, 15, 171-172; C. Szabo et al., Proc. Natl. Acad. Sci. USA1998, 95, 3867-3872; S. Cuzzocrea et al. Eur. J. Pharmacol. 1998, 342, 67-76). PARP is understood to include for the purpose of this invention isoenzymes of the PARP enzyme described above.
In addition, the PARP inhibitor 3-aminobenzamide showed protective effects in a model of circulatory failure (S. Cuzzocrea et al., Br. J. Pharmacol. 1997, 121, 1065-1074).
There is likewise experimental evidence that inhibitors of the enzyme PARP might be useful as agents for treating diabetes mellitus (V. Burkart et al. Nature Med. 1999, 5, 314-319).
Benzimidazoles have been described many times. Thus, DE 38 30 060 discloses alkylated derivatives as inhibitors of erythrocyte aggregation. DE 35 22 230 mentions an ester derivative of 2-phenylbenzimidazole as inhibitor of platelet aggregation. Halogen-substituted 2-phenylbenzimidazoles having substituted amine radicals on the phenyl ring have been described in WO 98/06703 as MCP-1 antagonists.
Likewise known are 2-phenylbenzimidazoles in which the benzimidazole group is substituted by an amide group. 5-amido derivatives of 2-phenylbenzimidazole with alkyloxy radicals on the phenyl ring have been described in WO 94/12461 as inhibitors of cAMP phosphodiesterase. It was found in DE 35 46 575 (e.g. Example 15) for analogous derivatives that these compounds induce positive inotropic effects. 4-Amido derivatives having a pyridyl radical in position 3 are likewise mentioned in WO 97/48697 as inhibitors of cAMP phosphodiesterase.
Benzimidazoles with amido groups in position 4 and with heterocyclic rings in position 2 are likewise known, for example from Denn W. A. et al., J. Med. Chem. 1990, 33, 814-819. Described therein are, for example, benzimidazoles with thiophene ring, with pyridine rings, furan rings and pyrrole rings in position 2, although the amido groups in position 4 on the benzimidazole carry other alkylamino radicals, which is important for the cytotoxic effect mentioned therein, but these substitutions on the amide residue are extremely unfavorable for an inhibitory effect on the enzyme PARP and usually lead to inactive compounds (see page 728 in M. J. Suto et al., Drugs of the Future, 1991, 16, 723-739).
The synthesis of 2-phenyl-benzimidazole-4-carboxamides has been described in J. Chem. Soc. Perkin Trans 1, 1979, 2303-2307. Analogous compounds which have a substituted alkyl chain on the amide residue and are said to have a cytotoxic effect are mentioned in J. Med. Chem. 1990, 33, 814-819. WO 97/04771 mentions, on the other hand, benzimidazole-4-carboxamides which inhibit PARS. In particular, derivatives described therein as active have a phenyl ring in position 2, and the phenyl ring may also be substituted by simple substituents such as nitro, methoxy and CF3. Although some of these substances show good inhibition of the enzyme PARP, the derivatives described therein have the disadvantage that they show little or no solubility in aqueous solutions and thus cannot be administered as aqueous solution.
In a number of therapies, such as stroke, the active ingredients are administered intravenously as infusion solution. For this purpose it is necessary to have available substances, in this case PARP inhibitors, which have adequate solubility in water at physiological pH values or close pH values (for example pH values of 5-8) so that an infusion solution can be prepared. Many of the PARP inhibitors described, especially the more effective PARP inhibitors, have the disadvantage, however, that they have only low or no solubility in water at these pH values and thus are not suitable for intravenous administration. Active ingredients of this type can be administered only with excipients intended to confer solubility in water (cf. WO 97/04771). These excipients, for example polyethylene glycol and dimethyl sulfoxide, frequently cause side effects or are not tolerated. Very effective PARP inhibitors with adequate solubility in water have not previously been described.
Benzimidazoles with a carboxylic ester group or a carboxamide group in position 5 and, at the same time, heteroaromatic rings in position 2 have seldom been described, examples being thiazoles (JP 4001631) and quinolines (WO 9820007). Benzimidazoles having, for example, methyl groups on the benzo ring, or having further benzo rings fused on the benzo ring, or even being unsubstituted thereon, have frequently been described with heteroaromatic rings in position 2, for example indoles (V. Ketarev et al., Chem. Heterocycl. Comp. 1980, 16, 501-506), quinolines (J. Gosh, J. Ind. Chem. Soc. 1938, 15, 89), pyridines (T. Hisano, Chem. Pharm. Bull 1982, 30, 2996-3004), Pyrimidines (H. Bredereck et al., Chem. Ber. 1960, 93, 2410-2414) and pyrroles (GB 966,796).
Benzimidazoles with heteroaromatic rings such as pyridine, furan, thiophene and pyrrole in position 2 and with carboxylic acid derivatives in position 4 have been described in W. A. Denny et al., J. Med. Chem. 1990, 33, 814-819 as potential cytostatics. However, the carboxylic acid derivatives prepared and mentioned in this case are only the carboxylic acid itself and amides with alkylamine residues on the N atom.
It has been found, surprisingly, that benzimidazoles also having heteroaromatic rings on the imidazole ring and having a primary carboxamide group in position 4, that is to say in contrast to W. A: Denny et al (see above) no other radicals on the amide N atom, are very effective inhibitors of the enzyme PARP. It is possible by further incorporation of chemical radicals such as aliphatic amines in addition to achieve distinctly improved water solubility by salt formation, for example with acids.
The present invention describes novel benzimidazole derivatives of the general formulae I and II which show advantages over the previously described compounds and are potent PARP inhibitors, some of which also show adequate solubility in water allowing administration as infusion solution.
The present invention relates to substituted benzimidazoles of the general formulae I and II: 
in which
A is napthalene, a monocyclic aromatic, bicyclic and tricyclic aromatic or partly aromatic heterocyclic system comprising a maximum of 15 carbon atoms and up to 4 heteroatoms selected from the group of N,O,S, and rings may additionally carry up to 2 oxo groups, and A may also be substituted by up to three different or identical R3 radicals and additionally one R4 radical, and
R1 is hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C1-C6-alkyl, OH, nitro, CF3, CN, NR11R12, NHxe2x80x94COxe2x80x94R13, Oxe2x80x94C1-C4-alkyl, where R11 and R12 are, independently of one another, hydrogen or C1-C4-alkyl, and R13 is hydrogen, Cl-C4-alkyl, phenyl-Cl-C4-alkyl or phenyl, and
R2 is hydrogen, branched and unbranched C1-C6-alkyl and
R3 is hydrogen, chlorine, bromine, iodine, fluorine, CF3, OCF3, nitro, NH2, COxe2x80x94R8, CO2xe2x80x94R8, SO2-R8, OH, Oxe2x80x94C1-C4-alkyl, phenyl-C0-C4-alkyl-Oxe2x80x94, a C1-C6 chain which may be saturated, unsaturated or partially unsaturated and may also be substituted by an R33 radical, phenyl, where the phenyl rings may also be substituted by up to three identical or different R31 radicals, and pyridyl which may be substituted by up to three R32 radicals, and
R31 is OH, C1-C6-alkyl, Oxe2x80x94C1-C4-alkyl, chlorine, bromine, iodine, fluorine, CF3, nitro, NH2, and
R32 is OH, C1-C6-alkyl, Oxe2x80x94C1-C4-alkyl, chlorine, bromine, iodine, fluorine, CF3, nitro, NH2, CN, and
R33 is COxe2x80x94NHxe2x80x94R8, OH, Oxe2x80x94C1-C6-Alkyl, Oxe2x80x94COxe2x80x94R8, and
R4 xe2x80x94(D)pxe2x80x94(E)sxe2x80x94(CH2)q xe2x80x94B, where
D is S, NR43 and O
E is phenyl and
s is 0 and 1 and
B is NR41R42 and 
and
p can be 0 and 1, and
q can be 0, 1, 2, 3 or 4, and
R41 can be hydrogen, C1-C6-alkyl, (CH2)rxe2x80x94G, and
R42 can be hydrogen, C1-C6-alkyl, xe2x80x94COxe2x80x94R8, SO2xe2x80x94R8, CO2xe2x80x94R8, xe2x80x94(Cxe2x95x90NH)xe2x80x94R8 and xe2x80x94(Cxe2x95x90NH)xe2x80x94NHR8 and
R41 and R42 can form a phthaloyl radical and
R43 can be hydrogen and C1-C4-alkyl and
r can be 0,1,2,3,4 and
G can be phenyl, which may also carry a maximum of two radicals R, NR11R12, phenyl-C1-C4-alkyl-NH, pyrrolidine, piperidine, 1,2,5,6-tetrahydropyridine, morpholine, homopiperidine, piperazine, which may also be substituted by an alkyl radical C1-C6-alkyl, and homopiperazine, which may also be substituted by an alkyl radical C1-C6-alkyl, and
R7 can be hydrogen, C1-C6-alkyl, phenyl, it also being possible for the ring to be substituted by up to two R71 radicals, and
R71 can be OH, C1-C6-alkyl, Oxe2x80x94C1-C4-alkyl, chlorine, bromine, iodine, fluorine, CF3, nitro, NH2, and
R8 can be C1-C6-alkyl, CF3, NR11R12, phenyl, phenyl-C1-C4-alkyl, it also being possible for the ring to be substituted by up to two R81 radicals, and
R81 can be OH, C1-C6-alkyl, Oxe2x80x94C1-C4-alkyl, chlorine, bromine, iodine, fluorine, CF3, nitro, NH2, and
R9 can be hydrogen, COxe2x80x94R8, SO2xe2x80x94R8, CO2xe2x80x94R8, C1-C6-alkyl, phenyl-C1-C4-alkyl and phenyl, it being possible for the phenyl ring also to be substituted by up to two R91 radicals, and
R91 can be OH, C1-C6-alkyl, Oxe2x80x94C1-C4-alkyl, chlorine, bromine, iodine, fluorine, CF3, nitro, NH2,
and their tautomeric forms, possible enantiomeric and diastereomeric forms, and their prodrugs.
Preferred compounds of the formula I and II are those where
R1 can be hydrogen and
R2 can be hydrogen and C1-C4-alkyl and
D can be NR43 and O and
p can be 0 and 1 and s can be 0 and q can be 0, 1 and 2, when p is 0, or q can be 2 and 3 when p is 1, and
R42 and R43 can be, independently of one another, hydrogen and C1-C4-alkyl and
R7 can be hydrogen and phenyl and
R9 can be hydrogen, C1-C4-alkyl and phenyl-COxe2x80x94C4-alkyl.
Preferred meanings of A are indole, benzimidazole, pyrrole, imidazole, furan, thiophene, benzothiophene, benzofuran, pyrazole, thiazole, benzothiazole, phthalimide, indazole, benzotriazole, phthalazine, indoline, isoindoline, pyridine, quinoline, pyrimidine, pyridazine, isoquinoline, quinoxaline, quinazoline, naphthalene, isooxazole, oxazole, imidazopyridine, pyrazine.
Preferred compounds of the formula I and II are those where A has the following meaning:
pyridine, thiophene, thiazole, furan, indole, oxazole, pyrazole, pyrrole, benzofuran, imidazole, benzothiophene, isoxazole, pyrazine, pyrimidine, pyridazine, quinoline and the heterocyclic system may be substituted by up to three R3 radicals and one R4 radical, where
R3 is hydrogen, chlorine, bromine, iodine, fluorine, COR8, CO2R8, SO2R8, a C1-C6 chain which may be saturated, unsaturated or partially saturated and may also be substituted by an Oxe2x80x94COxe2x80x94R8 group, or phenyl-C1-C6-alkyl, phenyl, where the phenyl rings may also be substituted by up to three identical or different R31 radicals, and pyridyl which may be substituted by up to three R32 radicals, and
R4 is hydrogen and (D)pxe2x80x94(E)sxe2x80x94(CH2)qxe2x80x94B, and R3 and R4 are not both hydrogen.
Preferred compounds of formula I and II are those where A has the following meaning:
pyridine, pyrazine, pyrimidine, pyridazine, quinoline, thiazole, thiophene, pyrrole and pyrazole and the heterocyclic system may be substituted by an R3 radical and an R4 radical, where
R3 is hydrogen, chlorine, bromine, iodine, fluorine, C1-C4-alkyl and
R4 is (D)pxe2x80x94(E)sxe2x80x94(CH2)qxe2x80x94B.
Particularly preferred compounds of formula I and II are those where A may be pyridine, thiophene and thiazole, and the heterocyclic system is substituted with an R4 radical where R4 is (D)pxe2x80x94(E)sxe2x80x94(CH2)qxe2x80x94B, and R3 is hydrogen.
The compounds of the formula I and II can be employed as racemates, as enantiomerically pure compounds or as diastereomers. If enantiomerically pure compounds are required, these can be obtained, for example, by carrying out a classical racemate resolution on the compounds of the formula I and II or their intermediates using a suitable optically active base or acid.
The invention also relates to compounds which are mesomers or tautomers of compounds of the formula I or II.
The invention further relates to the physiologically tolerated salts of the compounds I and II which can be obtained by reacting compounds I with a suitable acid or base. Suitable acids and bases are listed, for example, in Fortschritte der Arzneimittelforschung, 1966, Birkhxc3xa4user Verlag, volume 10, pp. 224-285. These include, for example, hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid etc., and sodium hydroxide, lithium hydroxide, potassium hydroxide and tris.
Prodrugs mean compounds which are metabolized in vivo to compounds of the general formula I and II. Typical prodrugs are phosphates, carbamates of amino acids, esters and others.
Benzimidazoles I and II according to the invention can be prepared in various ways as outlined in synthesis schemes 1-3. 
Condensation of the aldehyde with phenylenediamines gives the benzimidazole VII, this preferably being done in polar solvents such as ethanol or dimethylformamide with the addition of acids such as acetic acid at elevated temperature, usually 80 to 120xc2x0 C. It is beneficial for the reaction to add weak oxidizing agents such as copper(II) salts, which are added as aqueous solution. 
When R is NH2 in the phenylenediamine VIII, the condensation directly results in compounds I according to the invention. Otherwise, if R is O-alkyl, this ester can be reacted with ammonia, where appropriate at elevated temperature and under elevated pressure, to give the amide I. Alternatively, the ester VIII can be reacted with hydrazine in polar solvents such as the alcohols butanol and ethanol or else dimethylformamide at elevated temperatures, preferably 80-130xc2x0 C., to result in a hydrazide VIII (Rxe2x95x90NHNH2), which can then be reduced to the amide I under reducing conditions such as with Raney nickel in alcohols under reflux. 
As an alternative to the aldehydes VI shown in Scheme 1, it is also possible to employ acids such as XI (see Scheme 2) or nitrites such as XIV (see Scheme 3) in place of the aldehyde. Preparation of these derivatives takes place in analogy to the preparation of the substituted aldehydes VI. Starting from XI, the condensation to VII takes place in two stages. Firstly the acid XI is reacted with the aniline VIII in a peptide-like coupling to give the amide XII. The usual conditions are employed for this, as listed, for example, in Houben-Weyl, Methoden der Organischen Chemie, 4th edition, E5, chapter V and R. C. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 972 et seq. The ring closure to the benzimidazole then takes place at elevated temperature, for example 60 to 180xc2x0 C., with or without solvents such as dimethylformamide, with the addition of acids such as acetic acid or directly in acetic acid itself.
The reaction of the phenylenediamine VIII with a nitrile XIV likewise takes place under conventional conditions. This can be carried out in solvents such as dimethylformamide with the addition of acids or else in polyphosphoric acid at elevated temperature such as 60 to 200xc2x0 C. However, it is also possible to use conventional methods for preparing amidines from benzonitriles as described in Houben-Weyl, Methoden der Organischen Chemie, E5, pp. 1304 et seq., J. Amer. Chem. Soc. 1957, 427 and J. Org. Chem. 1987, 1017.
The abovementioned substituted benzimidazoles I and II are inhibitors of the enzyme poly(ADP-ribose) polymerase or PARP (EC 2.4.2.30).
The inhibitory effect of the substituted benzimidazoles I and II can be determined using an enzyme assay disclosed in the literature, with a Ki being determined as gauge of the effect. The benzimidazoles I and II were measured in this way for an inhibitory effect on the enzyme poly(ADP-ribose) polymerase or PARP (EC 2.4.2.30).
The substituted benzimidazoles of the general formulae I and II are inhibitors of poly(ADP-ribose) polymerase (PARP) or, as it is also known, poly(ADP-ribose) synthase (PARS), and can thus be used for the treatment and prophylaxis of diseases associated with an increased activity of these enzymes.
PARP isoenzymes are known in addition to the enzyme PARP, such as, for example, PARP II and PARP III (WO 99/64572).
The benzimidazoles I and II suprisingly also show an inhibitory effect on the enzyme PARP II.
A selective inhibition of PARP enzymes is desirable with a view to greater tolerability and fewer side effects of drugs.
Whereas the 2-phenylbenzimidazole-4-carboxamide (NU 1070) described in WO 97/04771 inhibits the enzymes PARP and PARP II with Ki values of the same order of magnitude, the benzimidazoles I and II show improved selectivities in the inhibition of PARP and PARP II.
The compounds of the formulae I and II can be employed to produce drugs for treating damage following ischemias and for the prophylaxis of expected ischemias in various organs.
The present benzimidazoles of the general formula I and II can accordingly be used for the treatment and prophylaxis of neurodegenerative disorders occurring after ischemia, trauma (craniocerebral trauma), massive bleeding, subarachnoid hemorrhages and stroke, and of neurodegenerative disorders such as multi-infarct dementia, Alzheimer""s disease, Huntington""s disease and of epilepsies, in particular of generalized epileptic seizures such as, for example, petit mal and tonoclonic seizures and partial epileptic seizures such as temporal lobe, and complex partial seizures, and further for the treatment and prophylaxis of damage to the heart after cardiac ischemias and damage to the kidneys after renal ischemias, for example of acute renal insufficiency, of acute kidney failure or of damage occurring during and after a kidney transplant. The compounds of the general formulae I and II can also be used to treat acute myocardial infarct and damage occurring during and after medical lysis thereof (for example with TPA, reteplase, streptokinase or mechanically with a laser or Rotablator) and microinfarcts during and after heart valve replacement, aneurysm resections and heart transplants. It is likewise possible to use the present benzimidazoles I and II for treatment in cases of revascularization of critically narrowed coronary arteries, for example in PTCA and bypass operations, and critically narrowed peripheral arteries, for example leg arteries. In addition, the benzimidazoles I and II can be beneficial in the chemotheraphy of tumors and metastasis thereof and can be used to treat inflammations and rheumatic disorders such as, for example, rheumatoid arthritis, and for the treatment of diabetes mellitus.
The pharmaceutical preparations according to the invention comprise a therapeutically effective amount of the compounds I and II in addition to conventional pharmaceutical excipients.
For local external use, for example in dusting powders, ointments or sprays, the active ingredients can be present in the usual concentrations. The active ingredients are ordinarily present in an amount of from 0.001 to 1% by weight, preferably 0.001 to 0.1% by weight.
On internal use, the preparations are administered in single doses. From 0.1 to 100 mg are given per kg of bodyweight in a single dose. The preparations may be administered in one or more doses each day, depending on the nature and severity of the disorders.
Appropriate for their required mode of administration, the pharmaceutical preparations according to the invention comprise conventional carriers and diluents in addition to the active ingredient. For local external use it is possible to use pharmaceutical excipients such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, liquid paraffin, petrolatum and wool fat. Examples suitable for internal use are lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone.
It is also possible for antioxidants such as tocopherol and butylated hydroxyanisole and butylated hydroxytoluene, flavor-improving additives, stabilizers, emulsifiers and lubricants to be present.
The substances present in the preparation in addition to the active ingredient, and the substances used in the production of the pharmaceutical preparations, are toxicologically acceptable and compatible with the particular active ingredient. The pharmaceutical preparations are produced in a conventional way, for example by mixing the active ingredient with conventional carriers and diluents.
The pharmaceutical preparations can be administered in various ways, for example orally, parenterally such as intravenously by infusion, subcutaneously, intraperitoneally and topically. Thus, possible presentations are tablets, emulsions, infusion and injection solutions, pastes, ointments, gels, creams, lotions, dusting powders and sprays.